RU2570382C1 - Pharmaceutical composition and medicinal agent based on clathrate complex of 7-brom-5-(ortho-chlorophenyl)-2,3-dihydro-1h-1,4-benzodiazepin-2-one and cyclodextrin, methods for producing it (versions) - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: there are described new clathrate complexes of 7-brom-5-(ortho-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one and cyclodextrin, which can find application in pharmaceutical industry, and methods for producing them. The invention also refers to compositions and medicinal agents based on the new clathrate complexes of 7-brom-5-(ortho-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one and cyclodextrin. To produce the complexes, α-, β- or γ-cyclodextrins, as well as hydroxypropyl-β-cyclodextrin can be used.

EFFECT: stability and high water solubility of the produced complexes and based pharmaceutical composition.

9 cl, 7 dwg, 8 ex, 1 tbl

Description

The invention relates to new pharmaceutical compositions based on clathrate complexes of 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one with cyclodextrin, which can be used in the pharmaceutical industry. The invention also relates to methods for their preparation of clathrate complexes of 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one with cyclodextrin.

To obtain complexes, α-, β- or γ-cyclodextrins, as well as hydroxypropyl-β-cyclodextrin, can be used.

7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one (Phenazepam) is a drug of the benzodiazepine group, first obtained in the USSR in 1974. It is widely used in medicine as a highly active tranquilizoranxiolytic (anti-anxiety) effect, also has an anticonvulsant, muscle-relaxing and hypnotic effect (S.B. Seredin. Phenazepam. 25 years in medical practice, (Scientific publication). Science, Moscow, 2007).

Significant disadvantages of this drug are poor solubility in water and low bioavailability.

One of the approaches to significantly improve bioavailability and increase solubility in water is to obtain clathrate (non-covalent) complexes.

A clathrate complex is a complex that is formed between molecules of substances due to the intermolecular van der Waals interaction of a non-covalent nature, namely, hydrogen bonding.

At present, at least ten carriers are known that make it possible to obtain stable clathrate complexes with high bioavailability, capable of converting water-insoluble pharmaceutical substances into water-soluble, for example, a variety of cyclodextrins having a toroidal shape, the inner cavity of which is hydrophobic. The formation of complexes occurs due to the intercalation of substance molecules in this cavity.

Complexes of β-cyclodextrin with non-steroidal anti-inflammatory drugs (paracetamol, ibuprofen, ketoprofen, flufenamic and mefenamic acids, etc.), steroids, prostaglandins and prostacyclins, barbiturates, sulfonamides, cardiac glycosides, and other drugs, for example, are available for treatment, for example, with U.S. Pat. US 4727064, RF patent 2337710, published in 2008, J. Szejtli, Industrial Applications of cyclodextrins. - InInclusion Compounds, v. 3. ed. Atwood JL, Davies JE, Mcnicob DD, Academic Press, NY., 1984, p. 331-390).

There are also many publications on inclusion compounds (clathrate complexes) of α- or β-cyclodextrins with antiviral compounds, methods for their preparation and use (see, for example, RF application 2005114097, RF patents 2288921, 2377243, 2247576, DE 19814815 A1, DE 19814814 A1, US 4956351, US 5221669, applications US 2005/0209189, US 2005/0281872, US 2009/0286757, JP 10-045319, JP 58-092691, JP-2005-179329, JP-9-015632).

In the article (II Krasnyuk et al. Increasing the solubility of Phenazepam by obtaining its solid dispersions. Chemical and Pharmaceutical Journal. Volume 44, No. 5, 2010) the effect of obtaining solid phenazepam dispersions with various carriers (polyvinylpyrrolidone, polyethylene glycol and β-cyclodextrin ) for solubility in water. It was shown that co-grinding Phenazepam with β-cyclodextrin in an analytical mill does not significantly improve solubility in water. Apparently, this is due to two factors:

1. The ratios of the components were mistakenly selected (in terms of moths, a portion of β-cyclodextrin does not “overlap” a portion of Phenazepam).

2. On the proposed equipment in the described conditions, clathrate “inclusion” complexes are not formed.

Therefore, in this case we can only talk about "fine" grinding.

An object of the present invention is to provide original clathrate complexes of cyclodextrins with 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one, which have increased solubility in water. The present invention also is the development of new methods for their preparation and use in pharmaceutical compositions and medicines.

The present invention provides original clathrate complexes (inclusion compounds) 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one, corresponding to general formula 1 with α-, β -, γ-cyclodextrins, hydroxypropyl - β-cyclodextrin, with a molar ratio of from 1: 1 to 1:10 (mass ratios from 1: 3 to 1:30).

The invention also relates to pharmaceutical compositions containing the above clathrate complex of β-cyclodextrin with 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one in molar ratios as defined above , in an effective amount, and a pharmaceutically acceptable excipient and / or excipient.

The invention also relates to a drug in the form of tablets and capsules in a pharmaceutically acceptable package containing a clathrate complex of β-cyclodextrin with 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine-2 -one at molar ratios indicated above, or pharmaceutical compositions based on them in an effective amount.

It was found that clathrate complexes are suitable for most dosage forms and routes of administration.

The term "effective amount" as used in this application means the use of that amount of a compound of formula 1 which, together with its activity indicators, must be effective in a given pharmaceutical composition or dosage form.

If necessary, the pharmaceutical composition may contain adjuvants, such as fillers, solvents, humectants, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors. Pharmaceutically acceptable additives may be selected, for example, from mannitol, microcrystalline cellulose, lactose, calcium stearate, magnesium stearate, starch. The choice and ratio of these components depends on the nature and method of administration and dosage.

The specified pharmaceutical composition and drug can be obtained by methods known in the pharmaceutical industry.

To obtain a pharmaceutical composition, the active ingredient (a compound of formula 1 as a clathrate complex with β-cyclodextrin) is mixed with a pharmaceutically acceptable carrier and, if necessary, with appropriate additives (carrier and / or excipients) to, for example, improve taste, odor.

Clathrate complexes can be obtained in two ways:

1) liquid-phase synthesis method and

2) solid-phase synthesis method.

The liquid phase method consists in preparing an aqueous solution of the corresponding starting cyclodextrin or hydroxypropyl-β-cyclodextrin and a solution of 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one in an organic solvent miscible with water, for example acetone. The resulting solutions are then mixed with stirring and kept at a temperature of from 55 to 60 ° C for 30 minutes, at a molar ratio of 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine- 2-one: cyclodextrin or hydroxypropyl-β-cyclodextrin from 1: 1 to 1:10 (mass ratios from 1: 3 to 1:30), followed by isolation of the product by any suitable method:

- using vacuum evaporation;

- using vacuum evaporation followed by lyophilization of the resulting solution;

- using vacuum evaporation followed by spray drying of the resulting solution.

It was found that it is precisely the temperature range from 55 to 60 ° C that makes it possible to obtain stable clathrate complexes of 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one with cyclodextrins with high yields (over 95%). If the temperature is lower than described, the rate of formation and stability of the complexes decreases, which may affect the quality of the final preparation. Otherwise, if the temperature exceeds the specified limits, the complex is destroyed (this fact is known from the literature). As the solvent, solvents or mixtures of solvents miscible with water, for example ethanol, isopropanol and the like, can be used.

According to the present method, clathrate complexes stabilized by hydrogen bonds are obtained.

The solid-phase method is that a mechanical mixture of cyclodextrin

(any of α, β, γ) or hydroxypropyl-β-cyclodextrin and 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one, molar ratios 7- bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one: cyclodextrin or hydroxypropyl-β-cyclodextrin from 1: 1 to 1:10 (mass ratios from 1: 3 until 1:30) is processed on a planetary ball mill in a shock-shear mode, i.e. the ratio of the rotation speed of grinding cups to the rotation speed of the planetary disk from 1.5 to 2.5 (depending on the design of the mill). The diameter of the grinding balls varies from 5 to 10 mm. The processing speed of the substance from 100 to 1500 rpm in the time interval from 10 to 60 minutes

The implementation of mechanochemical (solid-phase) synthesis is achieved due to the shock-shear regime, which allows you to obtain the optimal trajectory of the grinding bodies, which gives the maximum binding of 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4 -benzodiazepin-2-one in clathrate, as well as the tremendous acceleration of grinding media (up to 150 G) and also the high energy of their collision (approximately 80 N). The degree of formation of clathrate inclusion complexes is at least 95%. The undoubted advantage of the mechanochemical method is that it is not necessary to heat the substance (destruction is excluded), and the use of a solvent is also excluded.

In more detail, the invention is disclosed in the following examples, which illustrate the possibility of its implementation.

The resulting compounds have increased solubility in water, which is confirmed by the above data.

The following examples illustrate the invention.

Liquid phase method

Example 1. To a solution of 6 g (0.0171 mol) of 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one in 200 ml of acetone, stirred at boiling, was added heated to 60 ° C, a solution of 39 g (0.0342 mol) of β-cyclodextrin in 400 ml of distilled water. The reaction mass is stirred for 30 minutes, maintaining the temperature in the range of 55-60 ° C, after which it is naturally cooled to room temperature. The resulting reaction mass is evaporated to dryness on a rotary evaporator. After unloading, 26 g of substance are obtained in the form of a white powder.

Example 2. To a solution of 6 g (0.0171 mol) of 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one in 200 ml of ethanol, stirred at 60 ° C , a solution of 39 g (0.0342 mol) of β-cyclodextrin in 400 ml of distilled water is heated to 60 ° C. The reaction mass is stirred for 30 minutes, maintaining the temperature in the range of 55-60 ° C, after which it is naturally cooled to room temperature. The resulting solution is frozen. The residue is freeze-dried. After unloading, 25 g of the substance are obtained in the form of a white powder.

Example 3. To a solution of 6 g (0.0171 mol) of 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one in 200 ml of ethanol, stirred at 60 ° C A solution of 39 g (0.0342 mol) of hydroxypropyl-β-cyclodextrin in 400 ml of distilled water is added heated to 60 ° C. The reaction mass is stirred for 30 minutes, maintaining the temperature in the range of 55-60 ° C, after which it is naturally cooled to room temperature. Using a spray dryer, 23 g of substance are isolated in the form of a white powder.

Solid phase method

The tests were carried out on a planetary ball mill, grinding cups are lined with corundum, the material of the grinding balls used is zirconium oxide with diameters of 5 to 10 mm, shock-shear processing with a ratio of the rotation speed of the grinding cups to the rotation speed of the planetary disk from 1.5 to 2.5, the rotation speed of the disk ranged from 100 to 1500 rpm. The molar ratios of the components in the complex 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one: β-cyclodextrin ranged from 1: 1 to 1:10 (weight 1: 3 to 1:30), the molar ratios of 1: 2 and 1: 3 (weight 1: 6.5 and 1: 9.7) turned out to be optimal, the complexes were isolated in the form of a finely dispersed mobile powder of white color.

Example 4. A portion of 6 g (0.0171 mol) of 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one is mechanically mixed with 39 g (0.343 mol) β- cyclodextrin. The resulting mixture is divided in half and processed on a planetary ball mill for 5 minutes at a speed of 800 rpm, in a shock-shear mode, the ratio of the rotation speed of the grinding cups to the rotation speed of the planetary disk 2.0, the diameter of the balls is 5 mm. The resulting product is separated from the balls using a vibrating screen. Obtain 43 g of the complex in the form of a finely dispersed moving white powder.

Example 5. A portion of 6 g (0.0171 mol) of 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one is mechanically mixed with 58 g (0.0514 mol) β- cyclodextrin. The resulting mixture is divided in half and processed on a planetary ball mill for 5 minutes at a speed of 800 rpm, in a shock-shear mode, the ratio of the rotation speed of the grinding cups to the rotation speed of the planetary disk 2.0, the diameter of the balls is 5 mm. The product is separated from the balls using a vibrating screen. Obtain 52 g of the complex in the form of a fine moving white powder.

Example 6. A portion of 6 g (0.0171 mol) of 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one is mechanically mixed with 39 g (0.343 mol) β- cyclodextrin. The resulting mixture is divided in half and processed on a planetary ball mill for 10 minutes at a speed of 600 rpm, in a shock-shear mode, the ratio of the rotation speed of grinding grinding wheels to the rotation speed of the planetary disk is 1.5, and the diameter of the balls is 10 mm. The resulting product is separated from the balls using a vibrating screen. Obtain 43 g of the complex in the form of a finely dispersed moving white powder.

In addition to the above examples, tests were carried out on a ball mill (TC 21.00.000 PS), equipped with a china drum and agate balls.

Example 7. A portion of 60 g (0.0171 mol) of 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one is mechanically mixed with 580 g (0.514 mol) β- cyclodextrin. The resulting mixture is processed in a ball mill for 60 minutes at a speed of 68 rpm, the diameter of the balls is 25 mm The product is separated from the balls using a vibrating screen. Get 535 g of the complex in the form of a fine mobile powder of white color.

Example 8. A portion of 60 g (0.0171 mol) of 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one is mechanically mixed with 580 g (0.514 mol) β- cyclodextrin. The resulting mixture is processed in a ball mill for 30 minutes at a speed of 68 rpm, the diameter of the balls is 25 mm The product is separated from the balls using a vibrating screen. Get 536 g of the complex in the form of a finely dispersed moving white powder.

The following complexes were obtained:

7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one: α-cyclodextrin (molar ratios from 1: 1 to 1:10).

7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one: γ-cyclodextrin (molar ratios from 1: 1 to 1:10).

7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine: hydroxypropyl-β-cyclodextrin (molar ratios from 1: 1 to 1:10).

The formation of the obtained complexes was confirmed by UV and IR spectroscopy. The dissolution kinetics of the resulting complexes (liquid-phase and solid-phase synthesis methods) were studied by measuring the optical density of solutions containing an equal amount of pure substance 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine-2 -she. The tests were carried out according to the described procedure (II Krasnyuk et al. Increasing the solubility of Phenazepam by obtaining its solid dispersions. Chemical and Pharmaceutical Journal. Volume 44, No. 5, 2010).

It was shown that in the case of the complex 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one: β-cyclodextrin (molar ratio 1: 2) obtained by liquid phase by the method of Example 1 (hereinafter referred to as complex 1), the solubility in water reaches its maximum after 40 minutes (in terms of pure substance) and increases by more than 10 times, while the solubility of the complex is 7-bromo-5- (ortho-chlorophenyl) -2 , 3-dihydro-1H-1,4-benzodiazepin-2-one: β-cyclodextrin (molar ratio 1: 2) obtained by the solid-phase method according to example 4 (hereinafter complex 2), in water reaches its maximum after 20 minutes and increases compared to pure 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one by 40 times (Table 1).

Solubility measurements carried out in accordance with the State Pharmacopoeia of the Russian Federation, XII edition, showed that Phenazepam in the form of complex 2 passes from the “practically insoluble” category to the “very slightly soluble” category. The formation of the obtained complexes was confirmed by UV spectroscopy.

In the UV spectra of alcohol solutions 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one (Figure 2) and the studied complexes (weighed portions contained the same amount of 7-bromo- 5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one). In the case of complex 1 (Figure 3), a decrease in the intensity of the maximum at 321.8 nm is observed by a factor of two, and in the case of complex 2 (Figure 4) there is no maximum in this region.

In addition, a comparative analysis of the IR spectra of pure 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one (Figure 5), with spectra of complex 1 ( Figure 6) and complex 2 (Figure 7). All spectra were recorded in a disk with potassium bromine and contained the same amount (2 mg) of 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one. In the spectra of complex 1 and complex 2, the signals of the characteristic groups 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one overlap in the region from 4000 to 400 cm ^-1 . This fact suggests that the 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one molecule is located in the cavity of the β-cyclodextrin molecule, due to which a change in the spectral characteristics of the substance and unequivocally confirms the formation of clathrate complexes.

Comparable data were obtained with other examples.

TABLETS composition 1:

Complex 1 7.73 mg

Excipients: mannitol, microcrystalline cellulose, lactose, calcium stearate or magnesium stearate, starch.

Obtained by mixing the components in the mixer and pressing on a tabletting machine. Tablets are packaged in blister packs.

TABLETS composition 2:

Complex 2 3.86 mg

Excipients: mannitol, microcrystalline cellulose, lactose, calcium stearate or magnesium stearate, starch.

Obtained by mixing the components in the mixer and pressing on a tabletting machine. Tablets are packaged in blister packs. Dissolution of tablets - 100% after 10 minutes.

TABLETS composition 3:

Complex with α-cyclodextrin 10 mg

Excipients: mannitol, microcrystalline cellulose, lactose, calcium stearate or magnesium stearate, starch.

Obtained by mixing the components in the mixer and pressing on a tabletting machine. Tablets are packaged in blister packs. Dissolution of tablets - 100% after 10 minutes.

CAPSULES composition 1:

Complex with γ-cyclodextrin 15 mg

Excipients: mannitol, lactose, calcium stearate or magnesium stearate, starch.

Obtained by mixing the components in the mixer and filling the capsules on a capsule machine. Tablets are packaged in blister packs. Dissolution of capsules - 100% after 20 minutes.

INJECTION SOLUTION composition 1:

Complex with hydroxypropyl - β-cyclodextrin - 3 mg

Water for injection - up to 5 ml

Complex with hydroxypropyl - β-cyclodextrin - 3 mg is dissolved in a reactor in water for injection, poured into sterile ampoules with a final filter sterilization. Ampoules are sealed and labeled.

The data obtained are processed and presented in the form of graphs (Figure 1).

Claims (9)

1. A pharmaceutical composition containing a clathrate complex of 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one with cyclodextrin, obtained in a molar ratio of 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one: cyclodextrin from 1: 1 to 1:10, in an effective amount and a pharmaceutically acceptable excipient and / or excipient. 2. The clathrate complex of 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one with cyclodextrin in a molar ratio of 7-bromo-5- (ortho-chlorophenyl) - 2,3-dihydro-1H-1,4-benzodiazepin-2-one: cyclodextrin from 1: 1 to 1:10. 3. The clathrate complex of claim 2, wherein the cyclodextrin is α-, β-, γ- or hydroxypropyl-β-cyclodextrin. 4. The method of obtaining the clathrate complex of cyclodextrin with 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one according to claim 2 or 3, characterized in that it is pre-cooked an aqueous solution of the corresponding starting cyclodextrin and a solution of 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one in an organic solvent miscible with water are stirred at a temperature of from 55 to 60 ° C for 30 minutes with the isolation of the resulting clathrate complex by vacuum evaporation. 5. A method of obtaining a clathrate complex of cyclodextrin with 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one according to claim 2 or 3, characterized in that it is pre-cooked an aqueous solution of the corresponding starting cyclodextrin and a solution of 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one in an organic solvent miscible with water are stirred at a temperature of from 55 to 60 ° C for 30 minutes with the isolation of the obtained clathrate complex by vacuum evaporation followed by lyophilization obtained th solution. 6. A method of producing a clathrate complex of cyclodextrin with 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one according to claim 2 or 3, characterized in that it is pre-cooked an aqueous solution of the corresponding starting cyclodextrin and a solution of 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one in an organic solvent miscible with water are stirred at a temperature of from 55 to 60 ° C for 30 minutes, with the separation of the obtained clathrate complex by vacuum evaporation followed by spray drying the resulting solution. 7. A method of obtaining a clathrate complex of cyclodextrin with 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one according to claim 2 or 3, characterized in that the mechanical mixture cyclodextrin and 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one, molar ratios of 7-bromo-5- (ortho-chlorophenyl) -2,3- dihydro-1H-1,4-benzodiazepin-2-one: cyclodextrin from 1: 1 to 1:10 (mass ratios from 1: 3 to 1:30) is processed using a planetary ball mill using an impact-shear treatment mode with a ratio grinding bowl rotation speeds to ck grow planetary disc rotation of 1.5 to 2.5 at substance processing speed of 100 to 1500 rev / min in the range of from 10 to 60 minutes, provided that the diameter of the balls is between 5 and 10 mm. 8. A medicament containing the clathrate complex of 7-bromo-5- (ortho-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one with a cyclodextrin according to claim 2 or 3 or the pharmaceutical composition according to claim .1 in an effective amount, in the form of capsules or tablets or injection. 9. The drug according to claim 8, characterized in that said capsules or tablets or injection is in a pharmaceutically acceptable package.

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